Cytotoxic agents

ABSTRACT

The invention provides compounds of the invention pharmaceutical compositions comprising a compound of the invention, processes for preparing compounds of the invention, intermediates useful for preparing compounds of the invention, and therapeutic methods for treating cancer and other topoisomerase mediated conditions.

This application is a divisional of U.S. Ser. No. 10/846,936 filed onMay 14, 2004, now U.S. Pat. No. 7,319,105, which is a continuation under35 U.S.C 111 (a) of PCT/US02/36604, filed Nov. 14, 2002 and published inEnglish on May 22, 2003 as WO 03/041653 A2, which claimed priority under35 U.S.C. 119(e) of U.S. Provisional Application No. 60/332,733, filedNov. 14, 2001, U.S. Provisional Application No. 60/333,040, filed Nov.14, 2001, U.S. Provisional Application No. 60/332,698, filed Nov. 14,2001, U.S. Provisional Application No. 60/333,051, filed Nov. 14, 2001,and U.S. Provisional Application No. 60/332,970, filed Nov. 14, 2001,which applications and publications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

DNA-topoisomerases are enzymes which are present in the nuclei of cellswhere they catalyze the breaking and rejoining of DNA strands, whichcontrol the topological state of DNA. Recent studies also suggest thattopoisomerases are also involved in regulating template supercoilingduring RNA transcription. There are two major classes of mammaliantopoisomerases. DNA-topoisomerase-I catalyzes changes in the topologicalstate of duplex DNA by performing transient single-strand breakage-unioncycles. In contrast, mammalian topoisomerase II alters the topology ofDNA by causing a transient enzyme bridged double-strand break, followedby strand passing and resealing. Mammalian topoisomerase II has beenfurther classified as Type II α and Type II β. The antitumor activityassociated with agents which are topoisomerase poisons is associatedwith their ability to stabilize the enzyme-DNA cleavable complex. Thisdrug-induced stabilization of the enzyme-DNA cleavable complexeffectively converts the enzyme into a cellular poison.

Several antitumor agents in clinical use have potent activity asmammalian topoisomerase II poisons. These include adriamycin,actinomycin D, daunomycin, VP-16, and VM-26 (teniposide orepipodophyllotoxin). In contrast to the number of clinical andexperimental drugs which act as topoisomerase II poisons, there arecurrently only a limited number of agents which have been identified astopoisomerase I poisons. Camptothecin and its structurally-relatedanalogs are among the most extensively studied topoisomerase I poisons.Recently, bi- and terbenzimidazoles (Chen et al., Cancer Res. 1993, 53,1332-1335; Sun et al., J. Med. Chem. 1995, 38, 3638-3644; Kim et al., J.Med. Chem. 1996, 39, 992-998), certain benzo[c]phenanthridine andprotoberberine alkaloids and their synthetic analogs (Makhey et al.,Med. Chem. Res. 1995, 5, 1-12; Janin et al., J. Med. Chem. 1975, 18,708-713; Makhey et al., Bioorg. & Med. Chem. 1996, 4, 781-791), as wellas the fungal metabolites, bulgarein (Fujii et al., J. Biol. Chem. 1993,268, 13160-13165) and saintopin (Yamashita et al., Biochemistry 1991,30, 5838-5845) and indolocarbazoles (Yamashita et al., Biochemistry1992, 31, 12069-12075) have been identified as topoisomerase I poisons.Other topoisomerase poisons have been identified including certainbenzo[i]phenanthridine and cinnoline compounds (see LaVoie et al., U.S.Pat. No. 6,140,328 (735.037WO1), and WO 01/32631 (735.044WO1)). Despitethese reports there is currently a need for additional agents that areuseful for treating cancer.

SUMMARY OF THE INVENTION

Applicant has discovered compounds that show inhibitory activity againsttopoisomerase I and/or topoisomerase II, and compounds that areeffective cytotoxic agents against cancer cells, includingdrug-resistant cancer cells. Accordingly, the invention provides acompound of the invention which is a compound of formula I:

wherein:

A and B are independently N or CH;

Y and Z are independently hydroxy, (C₁-C₆)alkoxy, substituted(C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy, substituted (C₁-C₆) alkanoyloxy,—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); or Y and Z together with the ringcarbon atoms to which they are attached form an alkylenedioxy ring withfrom 5 to 7 ring atoms;

R₁ is (C₁-C₆)alkyl; and

R_(c) and R_(d) are each independently (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; or R_(c) and R_(d) together with the nitrogen to whichthey are attached form a N′—(C₁-C₆)alkylpiperazino, pyrrolidino, orpiperidino ring, which ring can optionally be substituted with one ormore aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention which is acompound of formula II:

wherein:

A and B are independently N or CH;

W is N or CH;

R₃ and R₄ are both H, or R₃ and R₄ together are ═O, ═S, ═NH or ═N—R₂wherein R₂ is (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl;

Y and Z are independently hydroxy, (C₁-C₆)alkoxy, substituted(C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy, substituted (C₁-C₆) alkanoyloxy,—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); or Y and Z together with the ringcarbon atoms to which they are attached form an alkylenedioxy ring withfrom 5 to 7 ring atoms;

R₁ is hydrogen or (C₁-C₆)alkyl; and

R_(c) and R_(d) are each independently (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; or R_(c) and R_(d) together with the nitrogen to whichthey are attached form a N′—(C₁-C₆)alkylpiperazino, pyrrolidino, orpiperidino ring, which ring can optionally be substituted with one ormore aryl, heteroaryl, or heterocycle;

provided that at least one or both A and B is N; and

provided that when R₃ and R₄ are both H then W is CH;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention which is acompound of formula III:

wherein:

X is O, S, NH, or ═N—R₂ wherein R₂ is (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl;

Y and Z are independently hydroxy, (C₁-C₆)alkoxy, substituted(C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy, substituted (C₁-C₆)alkanoyloxy,—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); or Y and Z together with the ringcarbon atoms to which they are attached form an alkylenedioxy ring withfrom 5 to 7 ring atoms;

R₁ is hydrogen or (C₁-C₆)alkyl; and

R_(c) and R_(d) are each independently (C₁-C₆)alkyl or substituted(C₁-₆)alkyl; or R_(c) and R_(d) together with the nitrogen to which theyare attached form a N′—(C₁-C₆)alkylpiperazino, pyrrolidino, orpiperidino ring, which ring can optionally be substituted with one ormore aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention which is acompound of formula IV:

wherein:

A and B are independently N or CH;

W is N or CH;

Y and Z are independently hydroxy, (C₁-C₆)alkoxy, substituted(C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy, substituted (C₁-C₆)alkanoyloxy,—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); or Y and Z together with the ringcarbon atoms to which they are attached form an alkylenedioxy ring withfrom 5 to 7 ring atoms;

R₁ and R₂ are independently H, (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl;or R₁ and R₂ together are ═O or ═S; and

R_(c) and R_(d) are each independently (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; or R_(c) and R_(d) together with the nitrogen to whichthey are attached form a N′—(C₁-C₆)alkylpiperazino, pyrrolidino, orpiperidino ring, which ring can optionally be substituted with one ormore aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention which is acompound of formula V:

wherein:

A and B are independently N or CH;

W is N or CH;

Y and Z are independently hydroxy, (C₁-C₆)alkoxy, substituted(C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy, substituted (C₁-C₆)alkanoyloxy,—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); or Y and Z together with the ringcarbon atoms to which they are attached form an alkylenedioxy ring withfrom 5 to 7 ring atoms;

R₁ and R₂ are independently H, (C₁-C₆)alkyl, or substituted(C₁-C₆)alkyl; or R₁ and R₂ together are ═O or ═S; and

R_(c) and R_(d) are each independently (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl; or R_(c) and R_(d) together with the nitrogen to whichthey are attached form a N′—(C₁-C₆)alkylpiperazino, pyrrolidino, orpiperidino ring, which ring can optionally be substituted with one ormore aryl, heteroaryl, or heterocycle;

or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising aeffective amount of a compound of the invention in combination with apharmaceutically acceptable diluent or carrier.

The invention also provides a method for modulating topoisomeraseactivity in a mammal in need of such treatment comprising administeringto the mammal, an amount of a compound of the invention effective toprovide a topoisomerase modulating effect.

The invention also provides a method of inhibiting cancer cell growth,comprising administering to a mammal afflicted with cancer, an amount ofa compound of the invention, effective to inhibit the growth of saidcancer cells.

The invention also provides a method comprising inhibiting cancer cellgrowth by contacting said cancer cell in vitro or in vivo with an amountof a compound of the invention, effective to inhibit the growth of saidcancer cell.

The invention also provides a compound of the invention for use inmedical therapy, preferably for use in treating cancer, for example,solid tumors, as well as the use of a compound of the invention for themanufacture of a medicament useful for the treatment of cancer, forexample, solid tumors.

The invention also provides processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention.

DETAILED DESCRIPTION

The following definitions are used, unless otherwise described.

“(C₁-C₆)alkyl” denotes both straight and branched carbon chains with oneor more, for example, 1, 2, 3, 4, 5, or 6, carbon atoms, but referenceto an individual radical such as “propyl” embraces only the straightchain radical, a branched chain isomer such as “isopropyl” beingspecifically referred to.

“Substituted (C₁-C₆)alkyl” is an alkyl group of the formula (C₁-C₆)alkylas defined above wherein one or more (e.g. 1 or 2) carbon atoms in thealkyl chain have been replaced with a heteroatom independently selectedfrom —O—, —S— and NR— (where R is hydrogen or C₁-C₆alkyl) and/or whereinthe alkyl group is substituted with from 1 to 5 substituentsindependently selected from cycloalkyl, substituted cycloalkyl,(C₁-C₆)alkoxycarbonyl (e.g. —CO₂Me), cyano, halo, hydroxy, oxo (═O),carboxy (COOH), aryloxy, heteroaryloxy, heterocyclooxy, nitro, and—NR^(a)R^(b), wherein R^(a) and R^(b) may be the same or different andare chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl,heterocycloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryland heterocyclic. Substituted (C₁-C₆)alkyl groups are exemplified by,for example, groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl,2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl,2-carboxyethyl, hydroxylated alkyl amines, such as 2-hydroxyaminoethyl,and like groups. Preferred substituted (C₁-C₆)alkyl groups are(C₁-C₆)alkyl groups substituted with one or more substituents of theformula-NR_(a)R_(b) where R_(a) and R_(b) together with the nitrogen towhich they are attached form of nitrogen containing heterocyclic ring.Specific examples of such heterocyclic rings include piperazino,pyrrolidino, piperidino, morpholino, or thiomorpholino. Other preferredsubstituted (C₁-C₆)alkyl groups are (C₁-C₆)alkyl groups substituted withone or more carbon-linked oxygen containing heterocyclic rings. Specificexamples of such oxygenated heterocyclic rings are, for example,tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, and like groups.

“(C₁-C₆)alkoxy” refers to groups of the formula (C₁-C₆)alkyl-O—, where(C₁-C₆)alkyl is as defined herein. Preferred alkoxy groups include, byway of example, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, andlike groups.

“Substituted (C₁-C₆)alkoxy” refers to a substituted (C₁-C₆)alkyl-O-groupwherein substituted (C₁-C₆)alkyl is as defined above. Substituted(C₁-C₆)alkoxy is exemplified by groups such as O—CH₂CH₂—NR_(a)R_(b),O—CH₂CH₂—CHR_(a)R_(b), or O—CH₂—CHOH—CH₂—OH, and like groups. Preferredsubstituted (C₁-C₆)alkoxy groups are (C₁-C₆)alkyl substituted with oneor more substituents of the formula-NR_(a)R_(b) where R_(a) and R_(b)together with the nitrogen to which they are attached form of aheterocyclic ring. Specific examples of such heterocyclic rings includepiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino.Other preferred substituted (C₁-C₆)alkoxy groups are (C₁-C₆)alkoxygroups substituted with one or more carbon-linked oxygen containingheterocyclic rings. Specific examples of preferred oxygenatedheterocyclic ring substituents are, for example, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups. Specific examples ofsuch oxygenated heterocyclic rings are, for example, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups.

“(C₁-C₆)alkanoyloxy” includes, by way of example, formyloxy, acetoxy,propanoyloxy, iso-propanoyloxy, n-butanoyloxy, tert-butanoyloxy,sec-butanoyloxy, n-pentanoyloxy, n-hexanoyloxy, 1,2-dimethylbutanoyloxy,and like groups.

“Substituted (C₁-C₆)alkanoyloxy” refers to a (C₁-C₆)alkanoyloxy groupwherein one or more (e.g. 1 or 2) carbon atoms in the alkyl chain havebeen replaced with a heteroatom independently selected from —O—, —S— andNR— (where R is hydrogen or C₁-C₆alkyl) and/or wherein the alkyl groupis substituted with from 1 to 5 substituents independently selected fromcycloalkyl, substituted cycloalkyl, (C₁-C₆)alkoxycarbonyl (e.g. —CO₂Me),cyano, halo, hydroxy, oxo (═O), carboxy (COOH), aryloxy, heteroaryloxy,heterocyclooxy, nitro, and —NR^(a)R^(b), wherein R^(a) and R^(b) may bethe same or different and are chosen from hydrogen, alkyl, arylalkyl,heteroarylalkyl, heterocycloalkyl, cycloalkyl, substituted cycloalkyl,aryl, heteroaryl and heterocyclic Substituted (C₁-C₆)alkanoyloxy isexemplified by groups such as —O—C(═O)CH₂—NR_(a)R_(b), andO—C(═O)—CHOH—CH₂—OH. Preferred substituted (C₁-C₆)alkanoyloxy groups aregroups wherein the alkyl group is substituted with one or more nitrogenand oxygen containing heterocyclic rings such as piperazino,pyrrolidino, piperidino, morpholino, thiomorpholino, tetrahydrofuranyl,tetrahydropyranyl, 1,4-dioxanyl, and like groups.

Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclicradical having about nine to ten ring atoms in which at least one ringis aromatic. Examples of aryl include phenyl, indenyl, and naphthyl.

Heteroaryl encompasses a radical attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms each selected from the groupconsisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absentor is H, O, (C₁-C₄)alkyl, phenyl or benzyl, as well as a radical of anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, or tetramethylene diradical thereto.Examples of heteroaryl include furyl, imidazolyl, triazolyl, triazinyl,oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl,pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl(or its N-oxide), indolyl, isoquinolyl (or its N-oxide) and quinolyl (orits N-oxide).

The term “heterocycle” refers to a monovalent saturated or partiallyunsaturated cyclic non-aromatic group which contains at least oneheteroatom, preferably 1 to 4 heteroatoms, selected from nitrogen(NR_(x), wherein R_(x) is hydrogen, alkyl, or a direct bond at the pointof attachment of the heterocycle group), sulfur, phosphorus, and oxygenwithin at least one cyclic ring and which may be monocyclic ormulti-cyclic. Such heterocycle groups preferably contain from 3 to 10atoms. The point of attachment of the heterocycle group may be a carbonor nitrogen atom. This term also includes heterocycle groups fused to anaryl or heteroaryl group, provided the point of attachment is on anon-aromatic heteroatom-containing ring. Representative heterocyclegroups include, by way of example, pyrrolidinyl, piperidinyl,piperazinyl, imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl,1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl and the like.

“Aryloxy” refers to a group of the formula aryl-O—, where aryl is asdefined herein. Examples of aryloxy groups include, phenoxy and1-naphthyloxy.

“Heteroaryloxy” refers to a group of the formula heteroaryl-O—, whereheteroaryl is as defined herein. Examples of heteroaryloxy groupsinclude, 3-piperidyloxy, 3-furyloxy, and 4-imidazolidinyl.

“Heterocyclooxy” refers to a group of the formula heterocycle-O—, whereheterocycle is as defined herein. Examples of heterocyclooxy groupsinclude, 4-morpholinooxy and 3-tetrahydrofuranyloxy.

“Arylalkyl” refers to a group of the formula aryl-(C₁-C₆)alkyl-, wherearyl and (C₁-C₆)alkyl are as defined herein.

“Heteroarylalkyl” refers to a group of the formulaheteroaryl-(C₁-C₆)alkyl-, where heteroaryl and (C₁-C₆)alkyl are asdefined herein.

“Heterocycloalkyl” refers to a group of the formulaheterocycle-(C₁-C₆)alkyl-, where heterocycle and (C₁-C₆)alkyl are asdefined herein.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

The Following Specific Values, Preferred Values, and Discussion Relateto Compounds of Formula I.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

-   -   A specific value for A is CH.    -   Another specific value for A is N.    -   A specific value for B is N.    -   Another specific value for B is CH.    -   A specific value for Y is OH.    -   Another specific value for Y is (C₁-C₆)alkoxy.    -   Another specific value for Y is —OCH₃.    -   Another specific value for Y is substituted (C₁-C₆)alkoxy.    -   Another specific value for Y is —OCH₂CH₂OH.    -   Another specific value for Y is —OCH₂CH₂OCH₂CH₃.    -   Another specific value for Y is —O—CH₂—CHOH—CH₂—OH.    -   Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein        R_(a) and R_(b) are hydrogen or (C₁-C₆)alkyl.    -   Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein        R_(a) and R_(b) together with the nitrogen to which they are        attached form a piperazino, pyrrolidino, piperidino, morpholino,        or thiomorpholino ring.    -   Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).    -   Another specific value for Y is —O—C(═O)—CHOH—CH₂—OH.    -   Another specific value for Y is (C₁-C₆)alkyl substituted with        one or more tetrahydrofuranyl, tetrahydropyranyl, or        1,4-dioxanyl rings.    -   Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).    -   A specific value for Z is OH.    -   Another specific value for Z is (C₁-C₆)alkoxy.    -   Another specific value for Z is OCH₃.    -   Another specific value for Z is substituted (C₁-C₆)alkoxy.    -   Another specific value for Z is —OCH₂CH₂OH.    -   Another specific value for Z is —OCH₂CH₂OCH₂CH₃.    -   Another specific value for Z is —O—CH₂—CHOH—CH₂—OH.    -   Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein        R_(a) and R_(b) are hydrogen or (C₁-C₆)alkyl.    -   Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein        R_(a) and R_(b) together with the nitrogen to which they are        attached form a piperazino, pyrrolidino, piperidino, morpholino,        or thiomorpholino ring.    -   Another specific value for Z is —O—C(═O)—CHOH—CH₂—OH.    -   Another specific value for Z is (C₁-C₆)alkyl substituted with        one or more tetrahydrofuranyl, tetrahydropyranyl, or        1,4-dioxanyl rings.    -   Another specific value for Z is —O—C(═O)CH₂—NR_(a)R_(b).    -   A specific value for R₁ is (C₁-C₆)alkyl.    -   Another specific value for R₁ is methyl, ethyl, propyl,        isopropyl, n-butyl, iso-butyl, n-pentyl, isopentyl, or n-hexyl.

A preferred compound of formula (I) is the compound12-ethyl-2,3-dimethoxy-12H-8,10-dioxa-6,12-diaza-cyclopenta[b]chrysen-13-one,12-butyl-2,3-dimethoxy-12H-8,10-dioxa-6,12-diaza-cyclopenta[b]chrysen-13-one,or a pharmaceutically acceptable salt thereof.

Certain compounds of formula (I) can function as prodrugs for othercompounds of formula (I). For example, a compound of formula (I) whereinY and/or Z is —O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); can function as aprodrug for a corresponding compound of formula (I) wherein Y and or Zis hydroxy. Accordingly, a specific sub set of compounds of formula (I)are compounds wherein Y and/or Z is —O—P(═O)(OH)₂, or—O—C(═O)NR_(c)R_(d). A particularly preferred compound is a compound offormula (I) wherein Y and/or Z is —O—P(═O)(OH)₂. Another preferredcompound is a compound of formula (I) wherein Y and/or Z is—O—C(═O)NR_(c)R_(d), wherein R_(c) and/or R_(d) is (C₁-C₆)alkylsubstituted with one or more —NR_(e)R_(f) wherein R_(e) and R_(f) areeach independently (C₁-C₆)alkyl. Another preferred compound is acompound of formula (I) wherein Y and/or Z is —O—C(═O)NR_(c)R_(d),wherein R_(c) and R_(d) together with the nitrogen to which they areattached form a N′-(alkyl)piperazino, pyrrolidino, or piperidino ring. Amore preferred compound is a compound of formula (I) wherein Y and/or Zis —O—C(═O)NR_(c)R_(d), wherein R_(c) and R_(d) together with thenitrogen to which they are attached form a piperidino ring, which ringis optionally substituted with an N-linked heterocycle (e.g. piperidino)ring.

The present invention provides compounds formula I and a method ofmaking compounds of formula I wherein R₁ is (C₁-C₆)alkyl or substituted(C₁-C₆)alkyl comprising reacting the compound of formula I where R₁ is Hwith a suitable nitrogen alkylating agent, such as an (C₁-C₆)alkylhalide or substituted (C₁-C₆)alkyl halide, to form a corresponding(C₁-C₆)alkyl or substituted (C₁-C₆)alkyl compound. It is understood byone skilled in the art that the lactam nitrogen atom can be convenientlysynthetically manipulated and efficiently converted into related usefulcompounds by, for example, preparing intermediate compounds with aprotected N atom and which protected nitrogen atom can be deprotectedand subsequently alkylated to provide the above mentioned alkylatednitrogen compounds.

A compound of formula I can be prepared by subjecting a correspondingintermediate of formula A to suitable cyclization conditions, forexample, by treatment with palladium acetate and tri-o-tolylphosphine,as illustrated in Scheme 1 below. A compound of formula I can also beprepared by subjecting a corresponding intermediate of formula B toconditions suitable for the formation of the ring system, for example,by treatment with a suitable tin reagent, as illustrated in Scheme 2below. Compounds of the present invention include intermediates offormulas A and B.

Other conditions suitable for formation of the ring system fromintermediates of formula A and formula B are well known to the art. Forexample, see Feiser and Feiser, “Reagents for Organic Synthesis”, Vol.1, 1967; March, J. “Advanced Organic Chemistry”, John Wiley & Sons, 4ed. 1992; House, H. O., “Modern Synthetic Reactions”, 2d ed., W. A.Benjamin, New York, 1972; and Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) edition, 1999, Wiley-VCH Publishers, New York.

An intermediate of formula A can be prepared from readily availablestarting materials using procedures that are known in the art, or can beprepared using the procedures illustrated below.

Chlorination of Compound 1 yields chloro-compound 2, which can beconverted to the corresponding amine by treatment with phenol andsubsequent reaction with the appropriate amine. The resulting amine canbe acylated with the appropriately substituted acylchloride to providethe intermediate of formula A.

An intermediate of formula B can be prepared from readily availablestarting materials using procedures that are known in the art, or can beprepared using procedures illustrated below.

Bromination of compound 1 provides compound 3, which can be converted tohalo-compound 4 using procedures known in the art. Reaction with asuitable amine or ammonium salt provides amino compound 5, which can beconverted to an intermediate of formula B by treatment with a suitableacid chloride 6.

The Following Specific Values, Preferred Values, and Discussion Relateto Compounds of Formula II.

Specific and preferred values listed below for radicals, substituents,and ranges, are for illustration only; they do not exclude other definedvalues or other values within defined ranges for the radicals andsubstituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Specifically, (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexoxy.

A specific value for A is CH.

Another specific value for A is N.

A specific value for B is N.

Another specific value for B is CH.

A specific value for W is N.

Another specific value for W is CH.

A specific value for Y is OH.

Another specific value for Y is (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₃.

Another specific value for Y is substituted (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₂CH₂OH.

Another specific value for Y is —OCH₂CH₂OCH₂CH₃.

Another specific value for Y is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

Another specific value for Y is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Y is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for Z is OH.

Another specific value for Z is (C₁-C₆)alkoxy.

Another specific value for Z is OCH₃.

Another specific value for Z is substituted (C₁-C₆)alkoxy.

Another specific value for Z is —OCH₂CH₂OH.

Another specific value for Z is —OCH₂CH₂OCH₂CH₃.

Another specific value for Z is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Z is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Z is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Z is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for both R₃ and R₄ is H.

A specific value for R₃ and R₄ together is ═O.

Another specific value for R₃ and R₄ together is ═S.

Another specific value for R₃ and R₄ together is ═NH.

Another specific value for R₃ and R₄ together is ═N—R₂.

Another specific value for R₃ and R₄ together is ═N—R₂ where R₂ is(C₁-C₆)alkyl.

Another specific value for R₃ and R₄ together is ═N—R₂ where R₂ issubstituted (C₁-C₆)alkyl.

A specific value for R₁ is hydrogen.

Another specific value for R₁ is (C₁-C₆)alkyl.

Another specific value for R₁ is isobutyl.

Another specific value for R₁ is n-butyl.

Another specific value for R₁ is isopentyl.

A specific value for R₂ is a (C₁-C₆)alkyl substituted with one or morehydroxy, mercapto, carboxy, amino, piperazinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or 1,4-dioxanyl groups.

Another specific value for R₂ is a (C₁-C₆)alkyl with from 2 to 4 carbonatoms and substituted with one to two groups selected from hydroxy,mercapto, carboxy, amino, piperazinyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or1,4-dioxanyl.

Another specific value for R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

A preferred compound of formula (II) is the compound12-butyl-2,3-dimethoxy-12H-8,10-dioxa-4,5,6,12-tetra-aza-cyclopenta[b]chrysen-13-one;12-butyl-2,3-dimethoxy-12H-8,10-dioxa-1,5,6,12-tetraaza-cyclopenta[b]chrysen-13-one;12-butyl-2,3-dimethoxy-12H-8,10-dioxa-1,4,5,6,12-penta-azacyclopenta[b]chrysen-13-one;or a pharmaceutically acceptable salt thereof.

Certain compounds of formula (II) can function as prodrugs for othercompounds of formula (II). For example, a compound of formula (II)wherein Y and/or Z is —O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); canfunction as a prodrug for a corresponding compound of formula (II)wherein Y and or Z is hydroxy. Accordingly, a specific sub set ofcompounds of formula (II) are compounds wherein Y and/or Z is—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d). A particularly preferred compoundis a compound of formula (II) wherein Y and/or Z is —O—P(═O)(OH)₂.Another preferred compound is a compound of formula (II) wherein Yand/or Z is —O—C(═O)NR_(c)R_(d), wherein R_(c) and/or R_(d) is(C₁-C₆)alkyl substituted with one or more —NR_(e)R_(f) wherein R_(e) andR_(f) are each independently (C₁-C₆)alkyl. Another preferred compound isa compound of formula (II) wherein Y and/or Z is —O—C(═O)NR_(c)R_(d),wherein R_(c) and R_(d) together with the nitrogen to which they areattached form a N′-(alkyl)piperazino, pyrrolidino, or piperidino ring. Amore preferred compound is a compound of formula (II) wherein Y and/or Zis —O—C(═O)NR_(c)R_(d), wherein R_(c) and R_(d) together with thenitrogen to which they are attached form a piperidino ring, which ringis optionally substituted with an N-linked heterocycle (e.g. piperidino)ring.

The present invention provides compounds formula II and a method ofmaking compounds of formula II wherein R₁ is such as (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl comprising reacting the compound of formula IIwhere R₁ is H with a suitable nitrogen alkylating agent, such as an(C₁-C₆)alkyl halide or substituted (C₁-C₆)alkyl halide, to form acorresponding (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl compound. It isunderstood by one skilled in the art that the lactam nitrogen atom canbe conveniently synthetically manipulated and efficiently converted intorelated useful compounds by, for example, preparing intermediatecompounds with a protected N atom and which protected nitrogen atom canbe deprotected and subsequently alkylated to provide the above mentionedalkylated nitrogen compounds.

A compound of formula II can be prepared by subjecting a correspondingintermediate of formula A to suitable cyclization conditions; forexample, by treatment with palladium acetate and tri-o-tolylphosphine,as illustrated in Scheme 1 below. A compound of formula II can beprepared by subjecting a corresponding intermediate of formula B toconditions suitable for the formation of the tetracyclic ring system;for example by treatment with a suitable tin reagent, as illustrated inScheme 2 below.

Other conditions suitable for formation of the ring system fromintermediates of formula A and formula B are well known to the art. Forexample, see Feiser and Feiser, “Reagents for Organic Synthesis”, Vol.1, 1967; March, J. “Advanced Organic Chemistry”, John Wiley & Sons,4^(th) ed., 1992; House, H. O., “Modern Synthetic Reactions”, 2d ed., W.A. Benjamin, New York, 1972; and Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) ed., 1999, Wiley-VCH Publishers, New York.

An intermediate of formula A can be prepared from readily availablestarting materials using procedures that are known in the art, or can beprepared using procedures illustrated below.

Similarly, an intermediate of formula B can be prepared from readilyavailable starting materials using procedures that are known in the art,or can be prepared using procedures illustrated below.

An alternative route to the formation of 5,6-dihydro derivatives offormula II involves either reduction of the lactam or desulfurization ofthe thioamide as illustrated by the following. Additionally, one canmodify compounds of formula II to provide other compounds of formula IIas illustrated below.

The Following Specific Values, Preferred Values, and Discussion Relateto Compounds of Formula III.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Specifically, (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexoxy.

A specific value for X is ═O.

Another specific value for X is ═S.

Another specific value for X is ═NH.

Another specific value for X is ═N—R₂.

Another specific value for X is ═N—R₂ where R₂ is (C₁-C₆)alkyl.

Another specific value for X is ═N—R₂ where R₂ is substituted(C₁-C₆)alkyl.

A specific value for Y is OH.

Another specific value for Y is (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₃.

Another specific value for Y is substituted (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₂CH₂OH.

Another specific value for Y is —OCH₂CH₂OCH₂CH₃.

Another specific value for Y is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

Another specific value for Y is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Y is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for Z is OH.

Another specific value for Z is (C₁-C₆)alkoxy.

Another specific value for Z is OCH₃.

Another specific value for Z is substituted (C₁-C₆)alkoxy.

Another specific value for Z is —OCH₂CH₂OH.

Another specific value for Z is —OCH₂CH₂OCH₂CH₃.

Another specific value for Z is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Z is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Z is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Z is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for R₁ is methyl, ethyl, propyl, or isopropyl.

A preferred compound of formula (III) is the compound12-butyl-2,3-dimethoxy-12H-8,10-dioxa-5,6,12-triaza-cyclopenta[b]chrysen-13-one,12-isobutyl-2,3-dimethoxy-12H-8,10-dioxa-5,6,12-triaza-cyclopenta[b]chrysen-13-one,or a pharmaceutically acceptable salt thereof.

Certain compounds of formula (III) can function as prodrugs for othercompounds of formula (III). For example, a compound of formula (III)wherein Y and/or Z is —O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); canfunction as a prodrug for a corresponding compound of formula (III)wherein Y and or Z is hydroxy. Accordingly, a specific sub set ofcompounds of formula (III) are compounds wherein Y and/or Z is—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d). A particularly preferred compoundis a compound of formula (III) wherein Y and/or Z is —O—P(═O)(OH)₂.Another preferred compound is a compound of formula (III) wherein Yand/or Z is —O—C(═O)NR_(c)R_(d), wherein R_(c) and/or R_(d) is(C₁-C₆)alkyl substituted with one or more —NR_(e)R_(f) wherein R_(e) andR_(f) are each independently (C₁-C₆)alkyl. Another preferred compound isa compound of formula (III) wherein Y and/or Z is —O—C(═O)NR_(c)R_(d),wherein R_(c) and R_(d) together with the nitrogen to which they areattached form a N′-(alkyl)piperazino, pyrrolidino, or piperidino ring. Amore preferred compound is a compound of formula (III) wherein Y and/orZ is —O—C(═O)NR_(c)R_(d), wherein R_(c) and R_(d) together with thenitrogen to which they are attached form a piperidino ring, which ringis optionally substituted with an N-linked heterocycle (e.g. piperidino)ring.

The present invention provides compounds formula III and a method ofmaking compounds of formula III wherein R₁ is such as (C₁-C₆)alkyl orsubstituted (C₁-C₆)alkyl comprising reacting the compound of formula Iwhere R₁ is H with a suitable nitrogen alkylating agent, such as an(C₁-C₆)alkyl halide or substituted (C₁-C₆)alkyl halide, to form acorresponding (C₁-C₆)alkyl or substituted (C₁-C₆)alkyl compound. It isunderstood by one skilled in the art that the lactam nitrogen atom canbe conveniently synthetically manipulated and efficiently converted intorelated useful compounds by, for example, preparing intermediatecompounds with a protected N atom and which protected nitrogen atom canbe deprotected and subsequently alkylated to provide the above mentionedalkylated nitrogen compounds.

A compound of formula III can be prepared by subjecting a correspondingintermediate of formula A to suitable cyclization conditions; forexample, by treatment with palladium acetate and tri-o-tolylphosphine,as illustrated in Scheme 1 below. A compound of formula III can also beprepared by subjecting a corresponding intermediate of formula B toconditions suitable for the formation of the ring system; for example bytreatment with a suitable tin reagent, as illustrated in Scheme 2 below.Compounds of the present invention include intermediates of formulas Aand B.

Other conditions suitable for formation of the ring system fromintermediates of formula A and formula B are well known to the art. Forexample, see Feiser and Feiser, “Reagents for Organic Synthesis”, Vol.1, 1967; March, J. “Advanced Organic Chemistry”, John Wiley & Sons,4^(th) ed., 1992; House, H. O., “Modern Synthetic Reactions”, 2d ed., W.A. Benjamin, New York, 1972; and Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) ed., 1999, Wiley-VCH Publishers, New York.

An intermediate of formula A can be prepared from readily availablestarting materials using procedures that are known in the art, or can beprepared using procedures illustrated below.

Similarly, an intermediate of formula B can be prepared from readilyavailable starting materials using procedures that are known in the art,or can be prepared using procedures illustrated below.

Alternatively, one can modify compounds of formula III to form relatedderivatives of formula III as illustrated by the following.

The Following Specific Values, Preferred Values, and Discussion Relateto Compounds of Formula IV.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Specifically, (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexoxy.

A specific compound of formula IV is a compound of formula XX:

Another specific compound of formula IV is a compound of formula XXI:

A specific value for W is N.

Another specific value for W is CH.

A specific value for A is CH.

Another specific value for A is N.

A specific value for B is N.

Another specific value for B is CH.

A specific value for Y is OH.

Another specific value for Y is (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₃.

Another specific value for Y is substituted (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₂CH₂OH.

Another specific value for Y is —OCH₂CH₂OCH₂CH₃.

Another specific value for Y is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

Another specific value for Y is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Y is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for Z is OH.

Another specific value for Z is (C₁-C₆)alkoxy.

Another specific value for Z is OCH₃.

Another specific value for Z is substituted (C₁-C₆)alkoxy.

Another specific value for Z is —OCH₂CH₂OH.

Another specific value for Z is —OCH₂CH₂OCH₂CH₃.

Another specific value for Z is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Z is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Z is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Z is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted with one ormore hydroxy groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone hydroxy group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more mercapto groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone mercapto group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more carboxy groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone carboxy group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more NR_(a)R_(b) groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone NR_(a)R_(b) group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more NH₂ groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone NH₂ group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more hydroxy, mercapto, carboxy, amino, piperazinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl with from 2 to 4carbon atoms and substituted with one to two groups selected fromhydroxy, mercapto, carboxy, amino, piperazinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or 1,4-dioxanyl.

Another specific value for R₁ or R₂ is 2-hydroxymethyl.

Another specific value for R₁ or R₂ is 2-hydroxyethyl.

Another specific value for R₁ or R₂ is 3-hydroxypropyl.

Another specific value for R₁ or R₂ is 2-hydroxypropyl.

Another specific value for R₁ or R₂ is H.

Another specific value for R₁ or R₂ is —CH₂—CHOH—CH₂—OH.

Another specific value for R₁ or R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a)and R_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for R₁ or R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a)and R_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for R₁ and R₂ together is ═O.

Another specific value for R₁ and R₂ together is ═S.

Another specific value for R₁ and R₂ together is ═NH.

A preferred compound of formula (IV) is the compound2,3-dimethoxy-13H-8,10,12-trioxa-5,6-diaza-cyclopenta[b]chrysene,2,3-dimethoxy-13H-8,10,12-trioxa-6-aza-cyclopenta[b]chrysene, or apharmaceutically acceptable salt thereof.

Certain compounds of formula (IV) can function as prodrugs for othercompounds of formula (IV). For example, a compound of formula (IV)wherein Y and/or Z is —O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); canfunction as a prodrug for a corresponding compound of formula (IV)wherein Y and or Z is hydroxy. Accordingly, a specific sub set ofcompounds of formula (IV) are compounds wherein Y and/or Z is—O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d). A particularly preferred compoundis a compound of formula (IV) wherein Y and/or Z is —O—P(═O)(OH)₂.Another preferred compound is a compound of formula (IV) wherein Yand/or Z is —O—C(═O)NR_(c)R_(d), wherein R_(c) and/or R_(d) is(C₁-C₆)alkyl substituted with one or more —NR_(e)R_(f) wherein R_(e) andR_(f) are each independently (C₁-C₆)alkyl. Another preferred compound isa compound of formula (IV) wherein Y and/or Z is —O—C(═O)NR_(c)R_(d),wherein R_(c) and R_(d) together with the nitrogen to which they areattached form a N′-(alkyl)piperazino, pyrrolidino, or piperidino ring. Amore preferred compound is a compound of formula (IV) wherein Y and/or Zis —O—C(═O)NR_(c)R_(d), wherein R_(c) and R_(d) together with thenitrogen to which they are attached form a piperidino ring, which ringis optionally substituted with an N-linked heterocycle (e.g. piperidino)ring. A compound of formula IV can be prepared by subjecting acorresponding intermediate of formula A to suitable cyclizationconditions; for example, by treatment with palladium acetate andtri-o-tolylphosphine, as illustrated in Scheme 1 below. A compound offormula IV can also be prepared by subjecting a correspondingintermediate of formula B to conditions suitable for the formation ofthe ring system; for example by treatment with a suitable tin reagent,as illustrated in Scheme 2 below. Compounds of the present inventioninclude intermediates of formulas A and B.

Other conditions suitable for formation of the ring system fromintermediates of formula A and formula B are well known to the art. Forexample, see Feiser and Feiser, “Reagents for Organic Synthesis”, Vol.1, 1967; March, J. “Advanced Organic Chemistry”, John Wiley & Sons, 4ed. 1992; House, H. O., “Modern Synthetic Reactions”, 2d ed., W. A.Benjamin, New York, 1972; and Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) edition, 1999, Wiley-VCH Publishers, New York.

An intermediate of formula A can be prepared from readily availablestarting materials using procedures known in the art, or can be preparedprocedures illustrated below.

Similarly, an intermediate of formula B can be prepared from readilyavailable starting materials using procedures known in the art, or canbe prepared using procedures illustrated below.

Alternatively, one can modify compounds of formula IV to form desiredderivatives related to formula IV as illustrated below.

The Following Specific Values, Preferred Values and Discussion Relate toCompounds of Formula V.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

Specifically, (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy,butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexoxy.

A specific compound of formula V is a compound of formula XXII:

or a pharmaceutically acceptable salt thereof.

Another specific compound of formula V is a compound of formula XXIII:

or a pharmaceutically acceptable salt thereof.

A specific value for W is N.

Another specific value for W is CH.

A specific value for A is CH.

Another specific value for A is N.

A specific value for B is N.

Another specific value for B is CH.

A specific value for Y is OH.

Another specific value for Y is (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₃.

Another specific value for Y is substituted (C₁-C₆)alkoxy.

Another specific value for Y is —OCH₂CH₂OH.

Another specific value for Y is —OCH₂CH₂OCH₂CH₃.

Another specific value for Y is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Y is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

Another specific value for Y is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Y is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Y is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for Z is OH.

Another specific value for Z is (C₁-C₆)alkoxy.

Another specific value for Z is OCH₃.

Another specific value for Z is substituted (C₁-C₆)alkoxy.

Another specific value for Z is —OCH₂CH₂OH.

Another specific value for Z is —OCH₂CH₂OCH₂CH₃.

Another specific value for Z is —O—CH₂—CHOH—CH₂—OH.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for Z is —O—CH₂CH₂—NR_(a)R_(b) wherein R_(a) andR_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for Z is —O—C(═O)—CHOH—CH₂—OH.

Another specific value for Z is (C₁-C₆)alkyl substituted with one ormore tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.

Another specific value for Z is —O—C(═O)CH₂—NR_(a)R_(b).

A specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted with one ormore hydroxy groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone hydroxy group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more mercapto groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone mercapto group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more carboxy groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone carboxy group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more NR_(a)R_(b) groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone NR_(a)R_(b) group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more NH₂ groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone NH₂ group.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl substituted withone or more hydroxy, mercapto, carboxy, amino, piperazinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl groups.

Another specific value for R₁ or R₂ is a (C₁-C₆)alkyl with from 2 to 4carbon atoms and substituted with one to two groups selected fromhydroxy, mercapto, carboxy, amino, piperazinyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl,tetrahydropyranyl, or 1,4-dioxanyl.

Another specific value for R₁ or R₂ is 2-hydroxymethyl.

Another specific value for R₁ or R₂ is 2-hydroxyethyl.

Another specific value for R₁ or R₂ is 3-hydroxypropyl.

Another specific value for R₁ or R₂ is 2-hydroxypropyl.

Another specific value for R₁ or R₂ is H.

Another specific value for R₁ or R₂ is —CH₂—CHOH—CH₂—OH.

Another specific value for R₁ or R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a)and R_(b) are hydrogen or (C₁-C₆)alkyl.

Another specific value for R₁ or R₂ is —CH₂CH₂—NR_(a)R_(b) wherein R_(a)and R_(b) together with the nitrogen to which they are attached form apiperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.

Another specific value for R₁ and R₂ together are ═O.

Another specific value for R₁ and R₂ together are ═S.

Another specific value for R₁ and R₂ together are ═NH.

A preferred compound of formula (V) is the compound2,3-dimethoxy-12H-8,10,13-trioxa-5,6-diaza-cyclopenta[b]chrysene,2,3-dimethoxy-12H-8,10,13-trioxa-6-aza-cyclopenta[b]chrysene, or apharmaceutically acceptable salt thereof.

Certain compounds of formula (V) can function as prodrugs for othercompounds of formula (V). For example, a compound of formula (V) whereinY and/or Z is —O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d); can function as aprodrug for a corresponding compound of formula (V) wherein Y and or Zis hydroxy. Accordingly, a specific sub set of compounds of formula (V)are compounds wherein Y and/or Z is —O—P(═O)(OH)₂, or—O—C(═O)NR_(c)R_(d). A particularly preferred compound is a compound offormula (V) wherein Y and/or Z is —O—P(═O)(OH)₂. Another preferredcompound is a compound of formula (V) wherein Y and/or Z is—O—C(═O)NR_(c)R_(d), wherein R_(c) and/or R_(d) is (C₁-C₆)alkylsubstituted with one or more —NR_(e)R_(f) wherein R_(e) and R_(f) areeach independently (C₁-C₆)alkyl. Another preferred compound is acompound of formula (V) wherein Y and/or Z is —O—C(═O)NR_(c)R_(d),wherein R_(c) and R_(d) together with the nitrogen to which they areattached form a N′-(alkyl)piperazino, pyrrolidino, or piperidino ring. Amore preferred compound is a compound of formula (V) wherein Y and/or Zis —O—C(═O)NR_(c)R_(d), wherein R_(c) and R_(d) together with thenitrogen to which they are attached form a piperidino ring, which ringis optionally substituted with an N-linked heterocycle (e.g. piperidino)ring. A compound of formula V can be prepared by subjecting acorresponding intermediate of formula A to suitable cyclizationconditions; for example, by treatment with palladium acetate andtri-o-tolylphosphine, as illustrated in Scheme 1 below. A compound offormula V can also be prepared by subjecting a correspondingintermediate of formula B to conditions suitable for the formation ofthe ring system; for example by treatment with a suitable tin reagent,as illustrated in Scheme 2 below. Compounds of the present inventioninclude intermediates of formulas A and B.

Other conditions suitable for formation of the ring system fromintermediates of formula A and formula B are well known to the art. Forexample, see Feiser and Feiser, “Reagents for Organic Synthesis”, Vol.1, 1967; March, J. “Advanced Organic Chemistry”, John Wiley & Sons, 4ed. 1992; House, H. O., “Modern Synthetic Reactions”, 2d ed., W. A.Benjamin, New York, 1972; and Larock, R. C., Comprehensive OrganicTransformations, 2^(nd) edition, 1999, Wiley-VCH Publishers, New York.

An intermediate of formula A can be prepared from readily availablestarting materials using procedures known in the art, or can be preparedusing at least two different procedures illustrated below.

Similarly, an intermediate of formula B can be prepared from readilyavailable starting materials using procedures that are known in the art,or can be prepared using procedures illustrated below.

Alternatively, one can modify these compounds to form the compounds offormula V as illustrated below.

General Discussion

The starting materials employed in the synthetic methods describedherein are commercially available, have been reported in the scientificliterature, or can be prepared from readily available starting materialsusing procedures known in the field. It may be desirable to optionallyuse a protecting group during all or portions of the above describedsynthetic procedures. Such protecting groups and methods for theirintroduction and removal are well known in the art. See Greene, T. W.;Wutz, P. G. M. “Protecting Groups In Organic Synthesis” second edition,1991, New York, John Wiley & Sons, Inc.

It will be appreciated by those skilled in the art that compounds of theinvention having a chiral center may exist in and be isolated inoptically active and racemic forms. Some compounds may exhibitpolymorphism. It is to be understood that the present inventionencompasses any racemic, optically-active, polymorphic, orstereoisomeric form, or mixtures thereof, of a compound of theinvention, which possess the useful properties described herein, itbeing well known in the art how to prepare optically active forms (forexample, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, or by chromatographic separation using a chiralstationary phase) and how to determine topoisomerase inhibition activityor cytotoxic activity using the standard tests described herein, orusing other similar tests which are well known in the art. Compounds ofthe present invention can contain chiral centers, for example, in any ofthe substituents Y, Z, and R₁.

In cases where compounds are sufficiently basic or acidic to form stablenontoxic acid or base salts, administration of the compounds as saltsmay be appropriate. Examples of pharmaceutically acceptable salts areorganic acid addition salts formed with acids which form a physiologicalacceptable anion, for example, tosylate, methanesulfonate, acetate,citrate, malonate, tartarate, succinate, benzoate, ascorbate,α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts mayalso be formed, including hydrochloride, sulfate, nitrate, bicarbonate,and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid affording aphysiologically acceptable anion. Alkali metal, for example, sodium,potassium or lithium, or alkaline earth metal, for example calcium,salts of carboxylic acids can also be made.

The compounds of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, that is, orally or parenterally, by intravenous,intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, forexample, orally, in combination with a pharmaceutically acceptablevehicle such as an inert diluent or an assimilable edible carrier. Theymay be enclosed in hard or soft shell gelatin capsules, may becompressed into tablets, or may be incorporated directly with the foodof the patient's diet. For oral therapeutic administration, the activecompound may be combined with one or more excipients and used in theform of ingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers, and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2 to about 60% of theweight of a given unit dosage form. The amount of active compound insuch therapeutically useful compositions is such that an effectivedosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form must be sterile, fluid and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompound in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfilter sterilization. In the case of sterile powders for the preparationof sterile injectable solutions, the preferred methods of preparationare vacuum drying and the freeze drying techniques, which yield a powderof the active ingredient plus any additional desired ingredient presentin the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of useful dermatological compositions which can be used todeliver the compounds of the invention to the skin are known to the art;for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S.Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman(U.S. Pat. No. 4,820,508).

Useful dosages of the compounds of the invention can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949.

Generally, the concentration of the compound(s) of the invention in aliquid composition, such as a lotion, will be from about 0.1-25 wt-%,preferably from about 0.5-10 wt-%. The concentration in a semi-solid orsolid composition such as a gel or a powder will be about 0.1-5 wt-%,preferably about 0.5-2.5 wt-%.

The amount of the compound, or an active salt or derivative thereof,required for use in treatment will vary not only with the particularsalt selected but also with the route of administration, the nature ofthe condition being treated and the age and condition of the patient andwill be ultimately at the discretion of the attendant physician orclinician.

In general, however, a suitable dose will be in the range of from about0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of bodyweight per day, such as 3 to about 50 mg per kilogram body weight of therecipient per day, preferably in the range of 6 to 90 mg/kg/day, mostpreferably in the range of 15 to 60 mg/kg/day.

The compound may conveniently be administered in unit dosage form; forexample, containing 5 to 1000 mg, conveniently 10 to 750 mg, mostconveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about30 μM. This may be achieved, for example, by the intravenous injectionof a 0.05 to 5% solution of the active ingredient, optionally in saline,or orally administered as a bolus containing about 1-100 mg of theactive ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

The ability of a compound of the invention to effect topoisomerase I orII mediated DNA cleavage can be determined using pharmacological modelsthat are well known to the art, for example, using a model like Test Adescribed below.

Test A. Topoisomerase I-mediated DNA Cleavage Assay

Human topoisomerase I was expressed in E. Coli and isolated as arecombinant fusion protein using a T7 expression system as describedpreviously, see Makhey, D. et al., Bioorg. Med. Chem., 2000, 8, 1-11.DNA topoisomerase I was purified from calf thymus gland as reportedpreviously, see Maniatis, T., et al., J. Molecular Cloning, a LaboratoryManual, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.,149-185). Plasmid YepG was also purified by the alkali lysis methodfollowed by phenol deproteination and CsCl/ethidium isopycniccentrifugation method as described, see Maniatis, T.; Fritsch, E. F.;Sambrook, J. Molecular Cloning, a Laboratory Manual; Cold Spring HarborLaboratory: Cold Spring Harbor, N.Y. 1982; pp 149-185. The end-labelingof the plasmid was accomplished by digestion with a restriction enzymefollowed by end-filling with Klenow polymerase as previously described,see Liu, L. F.; Rowe, T. C.; Yang, L.; Tewey, K. M.; Chen, G. L., J.Biol. Chem. 1983, 258, 15365. Cleavage assays were performed aspreviously reported, see B. Gatto et al. Cancer Res., 1996, 56,2795-2800. The drug and the DNA in presence of topoisomerase I wasincubated for 30 minutes at 37° C. After development of the gels,typically 24-hour exposure was used to obtain autoradiograms outliningthe extent of DNA fragmentation. Topoisomerase I-mediated DNA cleavagevalues are reported as REC, Relative Effective Concentration, i.e.concentrations relative to2,3-dimethoxy-8,9-methylenedioxybenzo[i]phenanthridine, whose value isarbitrarily assumed as 1.0, that are able to produce the same cleavageon the plasmid DNA in the presence of human topoisomerase I. Relativepotency was based upon the relative amount of drug needed to induceapproximately 10% DNA fragmentation. Assays are performed under thedirection of Dr. L. F. Liu, Department of Pharmacology, The Universityof Medicine and Dentistry of New Jersey, Robert Wood Johnson MedicalSchool, Piscataway, N.J.

A similar assay can be used to evaluate the ability of a compound of theinvention to effect topoisomerase II mediated DNA cleavage, by replacingthe human topoisomerase I used in Test A with a suitable topoisomeraseII.

The cytotoxic effects of a compound of the invention can be determinedusing pharmacological models that are well known to the art, forexample, using a model like Test B described below.

Test B. Inhibition of Cell Growth: MTT-microtiter Plate TetrazoliniumCytotoxicity Assay (RPMI 8402, CPT-K5, U937, U937/CR Cells)

The cytotoxicity is determined using the MTT-microtiter platetetrazolinium cytotoxicity assay (MTA), see Chen A. Y. et al. CancerRes. 1993, 53, 1332; Mosmann, T. J., J. Immunol. Methods 1983, 65, 55;and Carmichael, J. et al. Cancer Res. 1987, 47, 936. The humanlymphoblast RPMI 8402 and its camptothecin-resistant variant cell line,CPT-K5 were provided by Dr. Toshiwo Andoh (Anchi Cancer ResearchInstitute, Nagoya, Japan), see Andoh, T.; Okada, K, Adv. in Pharmacology1994, 29B, 93. Human U-937 myeloid leukemia cells and U-937/CR cellswere described by Rubin et al., J. Biol. Chem., 1994, 269, 2433-2439.The cytotoxicity assay is performed by using 96-well microtiter platesusing 2000 cells/well, in 200 mL of growth medium. Cells are grown insuspension at 37° C. in 5% CO₂ and maintained by regular passage in RPMImedium supplemented with 10% heat-inactivated fetal bovine serum,L-glutamine (2 mM), penicillin (100 U/mL), and streptomycin (0.1 mg/mL).For determination of IC₅₀, cells are exposed continuously for 3-4 daysto varying concentrations of drug, and MTT assays were performed at theend of the fourth day. Each assay is performed with a control that didnot contain any drug. All assays are performed at least twice in 6replicate wells. All assays are performed under the direction of Dr. L.F. Liu, Department of Pharmacology, The University of Medicine andDentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway,N.J.

The compounds of the invention can function as cytotoxic agents againsttumor cell lines, including multi-drug resistant tumor cell lines. Thus,the compounds are useful to treat cancer and can be used to treat tumorsthat are resistant to other specific chemotherapeutic agents.

Topoisomerase inhibitors are also known to possess antibacterial,antifungal, antipsoritic (psoriasis), antiprotozoal, antihelmetic, andantiviral activity. Accordingly, the topoisomerase inhibitors of theinvention may also be useful as antibacterial, antifungal, antipsoritic(psoriasis), antiprotozoal, antihelmetic, or antiviral agents. Inparticular, compounds of the invention that demonstrate little or noactivity as mammalian topoisomerase I poisons, because of thepossibility of similar molecular mechanism of action, could be highlyactive and selective antibacterial, antifungal, antipsoritic(psoriasis), antiprotozoal, antihelmetic, or antiviral agents. Thus,certain compounds of the invention may be particularly useful assystemic antibacterial, antifungal, antipsoritic (psoriasis),antiprotozoal, antihelmetic, or antiviral agents in mammals. Theinvention also provides the use of a compound of the invention for themanufacture of a medicament useful for producing an antibacterial,antifungal, antipsoritic (psoriasis), antiprotozoal, antihelmetic, orantiviral effect in a mammal.

As used herein, the term “solid mammalian tumors” include cancers of thehead and neck, lung, mesothelioma, mediastinum, esophagus, stomach,pancreas, hepatobiliary system, small intestine, colon, rectum, anus,kidney, ureter, bladder, prostate, urethra, penis, testis, gynecologicalorgans, ovarian, breast, endocrine system, skin central nervous system;sarcomas of the soft tissue and bone; and melanoma of cutaneous andintraocular origin. The term “hematological malignancies” includeschildhood leukemia and lymphomas, Hodgkin's disease, lymphomas oflymphocytic and cutaneous origin, acute and chronic leukemia, plasmacell neoplasm and cancers associated with AIDS. The preferred mammalianspecies for treatment are humans and domesticated animals.

The invention will now be illustrated by the following non-limitingExamples. Specific compounds of the present invention can be prepared asillustrated in the following schemes using known reactions and reagents.

EXAMPLE 1 Preparation of Representative Compounds of Formula I

EXAMPLE 2 Preparation of Representative Compounds of Formula I

Specific compounds of the present invention can be prepared inaccordance with the following schemes using known reactions andreagents.

EXAMPLE 3 Preparation of Representative Compounds of Formula II

EXAMPLE 4 Preparation of Representative Compounds of Formula II

EXAMPLE 5 Preparation of Representative Compounds of Formula III

EXAMPLE 6 Preparation of Representative Compounds of Formula III

EXAMPLE 7 Preparation of Representative Compounds of Formula IV

EXAMPLE 8 Preparation of a Representative Compound of Formula V

EXAMPLE 9 Preparation of a Representative Compound of Formula V

EXAMPLE 10 Synthesis of2,3-Dimethoxy-8,9-methylenedioxy-11-(n-butyl)-11H-5,6,11-triazachrysen-12-one

A mixture ofN-(6,7-Methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide(1.0 mmol equiv.), Pd(OAc)₂ (0.2 mmol equiv.), P(o-tolyl)₃ (0.4 mmolequiv.), and Ag₂CO₃ (2.0 mmol equiv) was heated to reflux in DMF (30 mLper mmol equiv.) with stirring. The reaction mixture was allowed to coolto room temperature, diluted with CHCl₃, and filtered through Celite.The sicciate was extensively washed with 10% CH₃OH in CHCl₃. Thefiltrate was concentrated in vacuo and the residue chromatographed onsilica gel using chlorofomm:methanol to provide the title compound (123mg, 0.2 mmol) in 27% yield with a reaction time 90 min; mp 299° C.; IR(KBr) 1654; ¹H NMR (CDCl₃) δ 1.06 (t, 3H, J=7.4), 1.56 (m, 2H), 2.13 (m,2H), 4.09 (s, 3H), 4.17 (s, 3H), 4.49 (m, 2H), 6.26 (s, 2H), 7.62 (s,1H), 7.85 (s, 1H), 7.87 (s, 1H), 8.65 (s, 1H); ¹³C NMR (CDCl₃) δ 13.8,20.2, 31.1, 48.6, 56.3, 56.6, 98.8, 102.7, 104.2, 106.5, 107.9, 119.7,149.1, 150.1, 150.9, 151.4, 153.6, 154.2, 162.9; HRMS calcd forC₂₂H₂₁N₃O₅H, 408.1559; found 408.1543

The intermediate compoundN-(6,7-Methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamidewas prepared as follows.

-   a. 6,7-Methylenedioxy-4-cinnolone. A mixture of    6′-amino-3′,4′-methylenedioxyacetophenone (2.4 g, 13.4 mmol) in    concentrated hydrochloric acid (92 mL) and water (13 mL) was cooled    to −5° C. and a diazotized by the dropwise addition of a solution of    sodium nitrite (0.925 g, 13.4 mmol) in water (4 mL). After stirring    for an additional hour at −5° C. the mixture was transferred to a    bath preheated at 75° C. and left to stir at this temperature    overnight. The reaction mixture was cooled to 5° C. to induce    crystallization. This material was filtered and then added to 10%    aqueous NaOH (100 mL), which was again filtered and dried under    vacuum to yield 2.37 g of the cinnoline as a colorless solid, in 93%    yield; mp 318-320° C.; ¹H NMR (DMSO-d₆) δ 6.21 (s, 2H), 6.97 (s,    1H), 7.30 (s, 1H), 7.63 (s, 1H); ¹³C NMR (DMSO-d₆) δ 94.9, 100.3,    103.3, 120.1, 139.7, 139.9, 147.4, 153.5, 169.4; HRMS calcd for    C₉H₆O₃N₂: 190.0378; found: 190.0372.-   b. 4-Chloro-6,7-methylenedioxycinnoline.    6,7-Methylenedioxy-4-cinnolone (1.0 g, 5.3 mmol) was added in small    portions to a stirred mixture of phosphorus pentachloride (1.4 g,    6.7 mmol) and phosphorus oxychloride (4 mL, 6.6 mmol) at room    temperature. The reaction flask was heated to 80° C. for 4 hours,    then cooled to room temperature and poured onto 50 g of crushed ice.    Following neutralization of the solution with solid sodium acetate,    the precipitate was removed by filtration and recrystallized from    ethanol to give 800 mg of the chlorocinnoline as an off-white solid,    in 73% yield; mp 203.5-204.5° C.; ¹H NMR (CDCl₃) δ 6.25 (s, 2H),    7.39 (s, 1H), 7.73 (s, 1H), 9.14 (s, 1H); ¹³C NMR (CDCl₃) δ 97.8,    102.9, 105.1, 124.2, 133.4, 144.0, 150.0, 152.3, 152.7; HRMS calcd    for C₉H₅O₂N₂Cl: 208.0040; found: 208.0042.-   c. N-(6,7-Methylenedioxycinnolin-4-yl)-n-butylamine. Butyl amine    ((25 ml)) was added with stirring to    4-chloro-6,7-methylenedioxycinnoline (1 g, 4.7 mmol) and copper    powder (250 mg). The reaction was then allowed to stir for 18 h at    80° C., and the solvent was removed under reduced pressure. The    residue was partitioned between CHCl₃ and 10% NaOH. The aqueous    layer was repeatedly separated with CHCl₃. All of the CHCl₃    solutions (initial partition and extracts) were combined and dried    (MgSO₄) to provide the product in 32.5% yield; mp 247-248° C.; ¹H    NMR (CDCl₃) δ 1.02 (t, 3H, J=7.4), 1.50 (m, 2H), 1.73 (m, 2H), 3.40    (m, 2H), 4.59 (s, 1H), 6.14 (s, 2H), 6.96 (s, 1H), 7.57 (s, 1H),    8.59 (s, 1H); ¹³C NMR (CDCl₃) δ 13.8; 20.2, 29.7, 31.3, 42.8, 94.2,    102.1, 105.3, 112.7, 126.7, 140.6, 149.6, 150.7; HRMS calcd for    C₁₃H₁₅N₃O₂H, 246.1243; found 246.1237.-   d.    N-(6,7-Methylenedioxycinnolin-4-yl)-N-(n-butyl)-2-iodo-4,5-dimethoxybenzamide.    A 2.0M solution of oxalyl chloride in CH₂Cl₂ (1.3 equiv.) was added    to a solution of 2-iodo-4,5-dimethoxybenzoic acid (1.0 equiv.) in    anhydrous CH₂Cl₂ (≈60 mL per 10 mmol benzoic acid) and the solution    stirred at reflux for 3 h. The mixture was allowed to cool and was    then concentrated to dryness in vacuo. To the residues was added a    solution of appropriate    N-(6,7-methylenedioxycinnolin-4-yl)-n-butylamine (1.0 equiv),    triethylamine (2 equiv.) in CH₂Cl₂ (≈60 mL per 4 mmol    aminoquinoline). The reaction mixture was then stirred at reflux    under N₂. The reaction mixture was cooled and washed with sat.    NaHCO₃ and extracted with 3% HCl. The aqueous layer was neutralized    with 20% NaOH and extracted with CHCl₃, dried (MgSO₄) and evaporated    to provide the product (350 mg, 1.4 mmol); in 19% yield with a    reaction time 18 h at 50° C. from the acid chloride prepared using    5.0 mmol of oxalyl chloride and 2.1 mmol of    2-iodo-4,5-dimethoxybenzoic acid; mp 133-134° C.; IR (KBr) 1654; ¹H    NMR (CDCl₃) δ 0.87 (t, 3H, J=7.2), 1.20-1.90 (m, 4H), 3.33 (s, 3H),    3.68 (s, 3H), 3.90 (m, 1H), 4.35 (m, 1H), 6.19 (d, 2H, J=3.2), 6.34    (s, 1H), 6.98 (s, 1H), 7.25 (s, 1H), 7.62 (s, 1H), 9.01 (s, 1H); ¹³C    NMR (CDCl₃) δ 13.7, 20.1, 30.0, 49.4, 55.7, 56.1, 82.9, 96.5, 102.9,    105.6, 110.5, 121.9, 133.1, 148.3, 150.0, 151.8, 152.5, 169.7; HRMS    calcd for C₂₂H₂₂IN₃O₅Li 542.0764; found 542.0757.

EXAMPLE 11 Synthesis of8,9-Dimethoxy-2,3-methylenedioxy-5-(butyl)-5H-dibenzo[c,h]1,6-naphthyridin-6-one

A mixture of theN-(6,7-Methylenedioxyquinolin-4-yl)-N-(butyl)-2-iodo-4,5-dimethoxybenzamide(1.0 mmol equiv.), Pd(OAc)₂ (0.2 mmol equiv.), P(o-tolyl)₃ (0.4 mmolequiv.), and Ag₂CO₃ (2.0 mmol equiv) was heated to reflux in DMF (30 mLper mmol equiv.) with stirring. The reaction mixture was allowed to coolto room temperature, diluted with CHCl₃, and filtered through Celite.The sicciate was extensively washed with 10% CH₃OH in CHCl₃. Thefiltrate was concentrated in vacuo and the residue chromatographed onsilica gel using chloroform:methanol to provide the title compound; (24%yield); reaction time 45 min; mp 224° C. (dec.); IR (KBr) 1654; ¹H NMR(CDCl₃); δ 0.99 (t, 3H, J=7.4), 1.62 (m, 2H), 2.09 (m, 2H), 4.07 (s,3H), 4.14 (s, 3H), 4.49 (m, 2H), 6.19 (s, 2H), 7.50 (s, 1H), 7.61 (s,1H), 7.70 (s, 1H), 7.92 (s, 1H), 9.40 (s, 1H); ¹³C NMR (CDCl₃) δ 13.7,20.2, 31.2, 50.6, 56.3, 56.4, 100.7, 102.0, 102.2, 107.4, 108.8, 111.7,114.9, 119.5, 127.4, 141.1, 143.7, 147.1, 147.5, 149.8, 150.3, 154.1,164.0; HRMS calcd for C₂₃H₂₂N₂O₅H, 406.1529; found 406.1534.

The intermediateN-(6,7-methylenedioxyquinolin-4-yl)-N-(butyl)-2-iodo-4,5-dimethoxybenzamidewas prepared as follows.

-   a. 4-Chloro-6,7-methylenedioxyquinoline. Was prepared from    4-hydroxy-6,7-methylenedioxyquinoline using methods as previous    described in the literature for the conversion of 4-hydroxyquinoline    to 4-chloroquinoline. Compound 5 had: mp 127.5-128° C. (Lit.²⁸ mp    129° C.); ¹H NMR (CDCl₃) 6.15 (s, 2H), 7.35 (d, 1H, J=4.7), 7.39 (s,    1H), 7.49 (s, 1H), 8.56 (d, 1H, J=4.7); ¹³C NMR (CDCl₃) 99.8, 102.2,    106.1, 119.9, 123.7, 129.8, 141.2, 147.7, 149.1, 151.4.-   b. N-(6,7-Methylenedioxyquinolin-4-yl)butylamine.    4-Chloro-6,7-methylenedioxyquinoline was stirred in refluxing phenol    (5.5 mol equiv.) for 2.5 h. The temperature was lowered to 100° C.    and butylamine (1.0 mol equiv.) was added with stirring. The    reaction was then allowed to stir at 100° C. for several hours, and    the phenol removed by Kugelrohr distillation under reduced pressure.    The residue was partitioned between CHCl₃ and 10% NaOH. The aqueous    layer was repeatedly separated with CHCl₃. All of the CHCl₃    solutions (initial partition and extracts) were combined and dried    (MgSO₄), and purified by column chromatography to provide the    product; mp 186-187° C.; ¹H NMR (CD₃OD) δ 1.02 (t, 3H, J=7.2), 1.52    (q, 2H, J=7.2), 1.75 (q, 2H J=7.2), 3.33 (q, 2H, J=7.2), 4.88 (b,    1H), 6.08 (s, 2H), 6.40 (d, 1H, J=5.6), 7.07 (s, 1H), 7.35 (s, 1H),    8.37 (d, 1H, J=6.0); ¹³C NMR (CH₃OD) δ 12.2, 19.3, 29.6, 42.3, 96.9,    97.3, 98.8, 102.3, 112.5, 138.7, 141.5, 147.3, 151.6, 152.8; HRMS    calcd for C₁₄H₁₆N₂O₂: 244.1212; found 244.1222.-   c.    N-(6,7-Methylenedioxyquinolin-4-yl)-N-(butyl)-2-iodo-4,5-dimethoxybenzamide.

A 2.0M solution of oxalyl chloride in CH₂Cl₂ (8.2 mmol) was added to asolution of 2-iodo-5,6-dimethoxybenzoic acid (1.9 mmol) in anhydrousCH₂Cl₂ (≈60 mL per 10 mmol benzoic acid) and the solution stirred atreflux for 3 h. The mixture was allowed to cool and was thenconcentrated to dryness in vacuo. To the residue was added a solution ofN-(6,7-Methylenedioxyquinolin-4-yl)butylamine (400 mg, 1.6 mmol),triethylamine (2 equiv.) in CH₂Cl₂ (≈60 mL per 4 mmol aminoquinoline).The reaction mixture was then stirred at reflux under N₂ for 72 h. Theresidue was partitioned between CHCl₃ and 10% NaOH. The aqueous layerwas repeatedly separated with CHCl₃. All of the CHCl₃ solutions (initialpartition and extracts) were combined and dried (MgSO₄). The aqueouslayer was neutralized with 20% NaOH and extracted with CHCl₃, dried(MgSO₄) and evaporated to provide the compound: ¹H NMR (CDCl₃) δ 0.85(t, 3H, J=7.4), 1.20-1.91 (m, 4H), 3.22 (s, 3H), 3.65 (s, 3H), 4.45 (m,2H), 6.08 (d, 2H, J=1.8), 6.31 (s, 1H), 6.97 (s, 1H), 7.17 (d, 1H,J=4.8), 7.29 (s, 1H), 7.30 (s, 1H), 8.49 (d, 1H, J=4.8).

EXAMPLE 12 8,9-Dimethoxy-2,3-methylenedioxy-6H-5-oxa-12-aza-chrysene

A mixture of4-(2-Iodo-4,5-dimethoxybenzyloxy)-6,7-methylenedioxyquinoline (186 mg,0.4 mmol), Pd(OAc)₂ (18 mg, 0.08 mmol), P(o-tolyl)₃ (49 mg, 0.16 mmol),and silver carbonate (220 mg, 0.8 mmol) was heated to reflux in DMF (12mL) and stirred under nitrogen for 25 minutes. The reaction mixture wascooled to room temperature, diluted with chloroform and filtered thougha bed of Celite. The filter was washed well with 90:10chloroform-methanol. Then the solvent was removed under reduced pressureand the resulting residue was chromatographed on silica gel usingchloroform to give the cyclized compound (30 mg) as a faintly pinksolid, in 23% yield; mp 239-242° C. (dec.); IR (CHCl₃) 3025, 3009, 2960,2928, 2855, 1603, 1526, 1496, 1463, 1346, 1285, 1260, 1243, 1219, 1210,1181, 1165, 1141, 1041; UV(THF) λ_(max)=222, 254, 282, 303, 326 (logε=3.98, 4.16, 4.22, 4.12, 4.14); ¹H NMR (CDCl₃) δ 3.95 (s, 3H), 4.01 (s,3H), 5.33 (s, 2H), 6.11 (s, 2H), 6.71 (s, 1H), 7.30 (s, 1H), 7.34 (s,1H), 7.42 (s, 1H), 8.95 (s, 1H); ¹³C NMR (CDCl₃) δ 56.3, 56.4, 68.9,97.6, 101.7, 106.0, 108.4, 112.6, 116.6, 120.9, 122.2, 143.4, 147.2,147.8, 149.4, 149.8, 150.9, 155.7; HRMS calcd for C₁₉H₁₅NO₅: 337.0950;found: 337.0945.

The intermediate compound4-(2-iodo-4,5-dimethoxybenzyloxy)-6,7-methylenedioxyquinoline wasprepared as follows.

-   a. Diethyl 3,4-methylenedioxyanilinomethylene malonate.    3,4-methylenedioxyaniline (41.0 g, 0.3 mmol) and diethyl    ethoxymethylenemalonate (64.8 g, 0.3 mmol) were refluxed in benzene    for 3.5 hours. The solvent was evaporated in vacuo and the residue    was washed with petroleum ether to give 88.3 g as a shiny grey-brown    solid, in 96% yield; mp 99.5-101.0° C. (lit.²²¹ mp 102° C.); ¹H NMR    (CDCl₃) δ 1.34 (t, 3H, J=7.0), 1.40 (t, 3H, J=7.0) 4.25 (q, 2H,    J=7.0), 4.31 (q, 2H, J=7.0), 6.01 (s, 2H), 6.60 (dd, 1H, J=8.5,    J=2.2), 6.71 (d, 1H, J=2.2), 6.81 (d, 1H, J=8.5), 8.41 (d, 1H,    J=14.0); ¹³C NMR (CDCl₃) δ 14.4, 14.6, 60.1, 60.4, 92.9, 99.4,    101.8, 108.9, 110.9, 134.3, 145.3, 148.9, 152.6, 165.8, 169.3.-   b. 4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid ethyl    ester. Diethyl 3,4-methylenedioxyanilinomethylene malonate (80.0 g,    0.261 mol) was stirred in polyphosphate ester (PPE) (250 g, 0.528    mol) at 120° C. with a mechanical stirrer for 2 hours. The reaction    mixture was poured into ice water (700 mL) and stirred until    homogenous. The mixture was then neutralized (pH 8) with ammonium    hydroxide, and the precipitate was filtered, washed well with water,    and dried to give 54.7 g as a brown solid, in 80% yield; mp 277-278°    C.; ¹H NMR (DMSO-d₆) δ 1.26 (t, 3H, J=7.0), 4.16 (q, 2H, J=7.0),    6.09 (s, 2H), 7.02 (s, 1H), 7.38 (s, 1H), 8.48 (s, 1H).-   c. 4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid.    4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid ethyl ester    (45.0 g, 0.172 mol) was added to a solution of KOH (16.8 g, 0.258    mol) in ethanol (500 mL) and the mixture was heated to reflux with    stirring for 20 hours. The reaction flask was then cooled and    ethanol was evaporated under reduced pressure. Then 800 mL of water    were added with stirring to fully dissolve the potassium salt, and    the solution was filtered to remove any impurities. Concentrated HCl    was added to bring the mixture to pH 1, and the free acid was    filtered off and dried under vacuum, to give 33.9 g as a beige    solid, in 84%; mp>300° C. (lit.²²¹ mp>290° C.); ¹H NMR (DMSO-d₆) δ    6.27 (s, 2H), 7.30 (s, 1H), 7.55 (s, 1H), 8.72 (s, 1H); ¹³C NMR    (DMSO-d₆) δ 98.5, 101.8, 103.8, 107.9, 120.8, 137.9, 143.5, 148.1,    153.7, 167.4, 177.4.-   d. 6,7-Methylenedioxy-4-quinolone. A suspension of    4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid (30 g, 0.129    mol) in diphenyl ether (320 mL) was heated to reflux with vigorous    stirring. The reaction was carefully monitored until it became    clear, about 1.5 h, and then immediately removed from heat. By this    time all of the starting material had dissolved but a black tarry    residue remained. The solution was decanted and cooled, allowing the    product to precipitate. This material was filtered and washed with    ethyl ether to remove all traces of phenyl ether. A second crop was    obtained by vigorously washing the tarry residue with ethanol    (16×250 mL), filtering and evaporating the ethanol, and rinsing the    material with ethyl ether. The total yield was 14.9 g as a pale    yellow solid, in 61%; mp 285-289° C. (lit.²²¹ mp 276° C.); ¹H NMR    (DMSO-d₆) δ 5.95 (d, 1H, J=7.3), 6.13 (s, 2H), 6.97 (s, 1H), 7.38    (s, 1H), 7.77 (d, 1H, J=7.3); ¹³C NMR (DMSO-d₆) δ 97.5, 102.1,    102.6, 108.7, 119.4, 122.0, 130.8, 138.7, 145.8, 151.7.-   e. 4-Chloro-6,7-methylenedioxyquinoline.    6,7-Methylenedioxy-4-quinolone (5.0 g, 26.5 mmol) was boiled in    POCl₃ (75 mL) for 45 min and then cooled. Excess phosphohoryl    chloride was removed under reduced pressure and ice water (100 mL)    was added to hydrolyze any residual phosphoryl chloride. The mixture    was basified (pH 9) with ammonium hydroxide, and the solid    precipitate was filtered. This material was extracted into ethyl    ether (8×100 mL), and the ether solution was dried (MgSO₄) and    evaporated to provide 4.55 g as a white solid, in 83%; mp    127.5-128° C. (lit.²²¹ mp 129° C.); ¹H NMR (CDCl₃) δ 6.15 (s, 2H),    7.35 (d, 1H, J=4.7), 7.39 (s, 1H), 7.49 (s, 1H), 8.56 (d, 1H,    J=4.7); ¹³C NMR (CDCl₃) δ 99.8, 102.2, 106.1, 119.9, 123.7, 129.8,    141.2, 147.7, 149.1, 151.4.-   f. 4-(2-Iodo-4,5-dimethoxybenzyloxy)-6,7-methylenedioxyquinoline. A    mixture of 4-Chloro-6,7-methylenedioxyquinoline (414 mg, 2.0 mmol),    2-Iodo-4,5-dimethoxybenzyl alcohol (586 mg, 2.0 mmol), and sodium    hydride (252 mg of a 60% dispersion, 6.0 mmol) in DMF (25 mL) was    stirred at 105° C. for 90 minutes. The mixture was cooled and a few    drops of water were added to quench the excess base. The solvent was    evaporated under reduced pressure and the residue was    chromatographed in chloroform to give 550 mg as a faintly yellow    solid, in 59% yield; mp 196-198° C.; ¹H NMR (DMSO-d₆) δ 3.78 (s,    3H), 3.81 (s, 3H), 5.22 (s, 2H), 6.19 (s, 2H), 7.07 (d, 1H, J=5.4),    7.30 (s, 1H), 7.32 (s, 1H), 7.33 (s, 1H), 7.41 (s, 1H), 8.55 (d, 1H,    J=5.4); ¹³C NMR (DMSO-d₆) δ 56.5, 56.8, 74.4, 89.3, 97.8, 102.2,    102.7, 105.9, 115.4, 116.2, 117.3, 122.8, 131.2, 147.8, 149.8,    149.9, 150.4, 151.2, 160.5; HRMS calcd for C₁₉H₁₆O₅NI: 465.0073;    found: 465.0076.

The intermediate 2-Iodo-4,5-dimethoxybenzyl alcohol was prepared asfollows.

-   g. 2-Iodo-4,5-dimethoxybenzyl alcohol. To a stirred mixture of    3,4-dimethyoxybenzyl alcohol (2.0 g, 11.9 mmol) and silver    trifluoroacetate (2.82 g, 12.9 mmol) in anhydrous methylene chloride    (50 mL) was dropwise added a solution of iodine (3.64 g, 14.1 mmol)    in methylene chloride (100 mL). After stirring at ambient    temperature for 2 hours, the reaction mixture was filtered and the    filtrate was washed with 5% NaHSO₃ (2×100 mL) and brine (100 mL),    dried (MgSO₄) and the solvent was evaporated under vacuum, to    provide 3.4 g as a white solid, in 97% yield; ¹H NMR (CDCl₃) δ 3.90    (s, 3H), 3.91 (s, 3H), 4.61 (s, 2H), 6.95 (s, 1H), 7.04 (s, 1H).

EXAMPLE 13

The following illustrate representative pharmaceutical dosage forms,containing a compound of the invention (‘Compound X’), for therapeuticor prophylactic use in humans.

(i) Tablet 1 mg/tablet ‘Compound X’ 100.0 Lactose 77.5 Povidone 15.0Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesiumstearate 3.0 300.0 (ii) Tablet 2 mg/tablet ‘Compound X’ 20.0Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate15.0 Magnesium stearate 5.0 500.0 (iii) Capsule mg/capsule ‘Compound X’10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch120.0 Magnesium stearate 3.0 600.0 (iv) Injection 1 (1 mg/ml) mg/ml‘Compound X’ (free acid form) 1.0 Dibasic sodium phosphate 12.0Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0 N Sodiumhydroxide solution (pH adjustment to 7.0-7.5) q.s. Water for injectionq.s. ad 1 mL (v) Injection 2 (10 mg/ml) mg/ml ‘Compound X’ (free acidform) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1Polyethylene glycol 400 200.0 01 N Sodium hydroxide solution (pHadjustment to 7.0-7.5) q.s. Water for injection q.s. ad 1 mL (vi)Injection 3 (1 mg/ml) mg/ml ‘Compound X’ (free base form) 1.0 CitricAcid 0.1% D5W q.s. ad 1 mL (vii) Aerosol mg/can ‘Compound X’ 20.0 Oleicacid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane10,000.0 Dichlorotetrafluoroethane 5,000.0

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound of formula II:

wherein: A or B is N and the other is CH; or A and B are each CH; W isN; R₃ and R₄ together are ═O, ═S, ═NH or ═N—R₂ wherein R₂ is(C₁-C₆)alkyl or substituted (C₁-C₆)alkyl; Y and Z are independentlyhydroxy, (C₁-C₆)alkoxy, substituted (C₁-C₆)alkoxy, (C₁-C₆)alkanoyloxy,substituted (C₁-C₆) alkanoyloxy, —O—P(═O)(OH)₂, or —O—C(═O)NR_(c)R_(d);or Y and Z together with the ring carbon atoms to which they areattached form an alkylenedioxy ring with from 5 to 7 ring atoms; R₁ ishydrogen or (C₁-C₆)alkyl; and R_(c) and R_(d) are each independently(C₁-C₆) alkyl or substituted (C₁-C₆) alkyl; or R_(c) and R_(d) togetherwith the nitrogen to which they are attached form aN′—(C₁-C₆)alkylpiperazino, pyrrolidino, or piperidino ring, which ringcan optionally be substituted with one or more aryl, heteroaryl, orheterocycle; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of claim 1 wherein A is N.
 3. The compound of claim 1 wherein Ais CH.
 4. The compound of claim 1 wherein A and B are each CH.
 5. Thecompound of claim 1 wherein Y is (C₁-C₆)alkoxy.
 6. The compound of claim1 wherein Y is —OCH₃.
 7. The compound of claim 1 wherein Y issubstituted (C₁-C₆)alkoxy.
 8. The compound of claim 1 wherein Z is(C₁-C₆)alkoxy.
 9. The compound of claim 1 wherein Z is OCH₃.
 10. Thecompound of claim 1 wherein Z is substituted (C₁-C₆)alkoxy.
 11. Thecompound of claim 1 wherein R₃ and R₄ together are ═O.
 12. The compoundof claim 1 wherein R₁ is hydrogen.
 13. The compound of claim 1 whereinR₁ is (C₁-C₆)alkyl.
 14. The compound of claim 1 wherein R₁ is isobutyl.15. The compound of claim 1 wherein R₁ is n-butyl.
 16. The compound12-butyl-2,3-dimethoxy-12H-8,10-dioxa-4,5,6,12-tetraaza-cyclopenta[b]chrysen-13-one;or12-butyl-2,3-dimethoxy-12H-8,10-dioxa-1,5,6,12-tetraaza-cyclopenta[b]chrysen-13-one;or a pharmaceutically acceptable salt thereof.
 17. The compound12-butyl-2,3-dimethoxy-12H-8,10-dioxa-5,6,12-triaza-cyclopenta[b]chrysen-13-one,12-isobutyl-2,3-dimethoxy-12H-8,10-dioxa-5,6,12-triaza-cyclopenta[b]chrysen-13-one,or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition comprising a compound as described in claim 1 in combinationwith a pharmaceutically acceptable diluent or carrier.
 19. A method ofinhibiting breast cancer cell growth, comprising administering to amammal afflicted with breast cancer, an amount of a compound asdescribed in claim 1 effective to inhibit the growth of said cancercells.
 20. A method comprising inhibiting breast cancer cell growth bycontacting said breast cancer cell in vitro or in vivo with an amount ofa compound as described in claim 1 effective to inhibit the growth ofsaid cancer cell.